Benign prostatic hyperplasia (BPH) is a disease mainly occurring in elder males aged 50 years or above and accompanying urinary disturbance, and its incidence rate increases as an increase in age. The number of patients with BPH in Japan has been constantly increasing in recent years with rapid aging of population structure (Non-patent Document 1). BPH remarkably deteriorates the quality of life of the aged males due to urinary disturbance, and it is an important disease in terms of medical economics since it is most frequently diagnosed and treated in medical practice in the department of urology.
It has been found that two factors, that is, direct urethral compression due to hypertrophy of the prostate (mechanical obstruction) and elevation of intraurethral pressure due to overcontraction of the prostatic smooth muscle via the sympathetic nerve (functional obstruction), are simultaneously involved in urinary disturbance accompanying BPH. Drug therapy can deal with the both of the mechanisms, and 5α-reductase inhibitors are mainly used for the mechanical obstruction and α-1-sympatholytic agents (α1 blockers) for the functional obstruction. 5α reductase inhibitors regress the prostate due to their anti-androgenic effect based on the suppression of conversion from testosterone to more potent 5α-dehydrotestosterone (DHT) of androgen by a 5α-reductase. Only the prostatic epithelium regresses, however, and it takes a long period of time (several weeks to several months) for its drug efficacy to appear. Since α1-blockers exert their drug efficacy swiftly after administration and are excellent in safety, on the other hand, α1-blockers are now the first-line agent for the treatment of BPH. Since long-term clinical studies of a 5α-reductase inhibitor have revealed, however, that the inhibitor preferentially delays the transfer to invasive therapy as compared with an α1-blocker used alone, and the like (Non-patent Document 2), the usefulness of 5α-reductase inhibitors has recently been recognized again.
It has been considered that DHT in the prostate is produced by 5α-reductase from testosterone, which is produced in the testes and secreted endocrinologically to the prostate. It has been reported recently, however, that about half of DHT and its precursor, testosterone in prostate are synthesized from dehydroepiandrosterone (DHEA), an adrenal steroid, in cells of the prostate (Non-patent Document 3). Such sex hormone production system in cells of the sex hormone target organs is called intracrinology.
It is difficult for 5α-reductase inhibitors to inhibit the local testosterone synthesis (intracrine testosterone synthesis) in the prostate. For example, it has been reported that the concentration of DHT in the prostate of the patients with BPH decreased after the administration of finasteride, a 5α-reductase inhibitor, to about 20% of the concentration before the administration, while the concentration of testosterone, a precursor, in the prostate increased 4-fold inversely (Non-patent Document 4). It means that although the 5α-reductase inhibitor has an effect of reducing DHT concentration in prostate, it has no effect of reducing the concentration of testosterone in prostate and elevates the concentration instead. Since testosterone has an androgen receptor binding activity in the order of half that of DHT, this local elevation of the concentrations of testosterone in prostate is considered to be partly attributable to insufficient drug efficacy of finasteride for BPH.
Anti-androgen therapies using surgical castration and gonadotropin releasing hormone agonists are also used for the treatment of prostatic cancer. These anti-androgen therapies have been reported to exert an insufficient effect of reducing the concentrations of testosterone in prostate. For example, in patients with prostatic cancer who receive the anti-androgen therapy, the concentration of testosterone in blood decreased to about 10% of the concentration before the therapy, while the concentration of dehydrotestosterone in prostate remained at about 50% (Non-patent Document 5). It suggests that the concentration of testosterone in prostate is neither reduced sufficiently. Further, androgen receptors were localized in nuclei also in a prostatic cancer recurring after anti-androgen therapy (hormone refractory prostate cancer), and no significant difference was observed between the concentration of testosterone in recurrent prostatic cancer tissue and that in the normal prostate (Non-patent Document 6). These reports strongly suggest that the effect of reducing the concentrations of testosterone in prostate in existing therapeutic methods is quite insufficient for the treatment of recurrent prostatic cancer and that suppression of the testosterone synthesizing mechanism in prostate, that is, intracrine testosterone synthesis in prostate may be a new target of the prostatic cancer therapy.
Based on the known arts described above, since inhibitors of intracrine testosterone synthesis in prostate have an effect of reducing the concentrations of testosterone in prostate and no effect of reducing the concentrations of testosterone in blood, the inhibitors are expected to be very attractive agents for the treatment of BPH, which can reduce not only the concentrations of testosterone but also the concentrations of DHT in prostate (1) and can avoid the adverse drug reactions due to the suppression of the concentrations of the testosterone in blood derived from testes (2).
17β-hydroxysteroid dehydrogenase (17βHSD) is essential for the biosynthesis of testosterone. There are several subtypes of 17β-hydroxysteroid dehydrogenase. 17β-hydroxysteroid dehydrogenase type 5 (17βHSD type 5) is highly expressed in a human prostate and the increases of the expression were reported for prostatic cancer and recurrent prostatic cancer (Patent Document 1, and Non-patent Documents 7, 18). On the other hand, almost all the testosterone in blood is biosynthesized by 17β-hydroxysteroid dehydrogenase type 3 (17βHSD type 3) in testes and the expression of 17βHSD type 3 is scarcely observed in other tissues including the prostate (Non-patent Document 8). 17βHSD type 5 is thus considered to be attributable to the intracrine testosterone synthesis in prostate and selective inhibitors for 17βHSD type 5 are expected to suppress intracrine testosterone synthesis in prostate selectively. Further, since attribution of 17βHSD type 5 has been pointed out also in estrogen-dependent tissues such as the breast and the like, the selective inhibitors are expected to be effective for estrogen-dependent diseases such as breast cancer and the like (Patent Document 1 and Non-patent Document 9). In addition, since AKR1C3 (another name for 17βHSD type 5), which is a subtype of aldo-keto reductase (AKR), metabolizes polycyclic aromatic hydrocarbon (PAH) to generate reactive oxygen species (ROS) (Non-patent Document 10) and since single nucleotide polymorphism (SNP) of AKR1C3 gene relating to oxidation stress correlates to a risk of lung cancer (Non-patent Document 11), it is suggested that the activity of AKR1C3 in the lungs increases a risk of lung cancer via biosynthesis of ROS from PAH. Selective inhibitors of 17βHSD type 5 are expected to be effective for lung cancer.
As 17βHSD type 5 inhibitors, steroid derivatives (Patent Document 1) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as flufenamic acid, indomethacin and the like (Non-patent Document 12), cinnamic acid derivatives (Non-patent Document 20) and the like have been reported. Although the mechanism of action is different, a certain type of indazole derivative is known to be effective for BPH (Patent Document 7). However, it has not been known that indole derivatives such as the compound of the present invention inhibit 17βHSD type 5 and are effective for BPH.
At the same time, although a certain type of indole compound is known to be effective for Ehrlich ascites cancer (Non-patent Document 19), they are not known to be effective for another type of cancer, prostatic cancer and BPH. In addition, although the known compounds described below having structures similar to the structure of the compound of the present invention are excluded from the compound of the present invention, the compounds described below are not known to be used for the treatment or prevention of the diseases described for the present invention.

Patent Document 1: International Publication WO99/46279
Patent Document 2: International Publication WO03/68220
Patent Document 3: International Publication WO96/36611
Patent Document 4: International Publication WO99/50245
Patent Document 5: International Publication WO97/48697
Patent Document 6: Japanese Patent Laid-open No. H09-104675
Patent Document 7: International Publication WO2004/064735
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Non-patent Document 8: Nature Genetics, 1994, Vol. 7, p. 34-39
Non-patent Document 9: Endocrine Reviews, 2003, Vol. 24, p. 152-182
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Non-patent Document 19: Archiv der Pharmazie—Pharmaceutical and Medicinal Chemistry, 1984, Vol. 317, p. 847-851
Non-patent Document 20: Molecular and Cellular Endocrinology, 2006, Vol. 248, p. 233-235